Critical Psychiatry Textbook, Chapter 8: Depression and Mania (Affective Disorders) (Part Ten)

Editor’s Note: Over the next several months, Mad in America is publishing a serialized version of Peter Gøtzsche’s book, Critical Psychiatry Textbook. In this blog, he discusses the diagnosis of bipolar disorder, including in children, and the lack of evidence for any benefit from lithium. Each Monday, a new section of the book is published, and all chapters are archived here.

Bipolar disorder

The hospital-based psychiatry center in one of the five regions in Denmark mentions on its homepage that “Drugs for bipolar disorder—mood stabilising drugs—can prevent and cure depression, mania and mixed conditions in most people.”⁴¹⁶

This is very misleading. Psychiatric drugs only have symptomatic effects. They are not disease-modifying and they cannot cure people; they can only lessen some of the symptoms of the emotional pain. Similarly, aspirin cannot cure a broken leg, only lessen the physical pain. Psychiatric drugs cannot prevent psychiatric disorders either.

About bipolar in children, a textbook said that the risk is increased if the children have had hypomanic or manic symptoms after treatment with a depression pill, and that there is a “family relation” between ADHD and bipolar.^19:216 It is not clear what the authors meant by this, e.g. if it is a genetic or environmental issue they describe. They did not mention that the harms of ADHD drugs are much the same as the diagnostic criteria for bipolar, and that many children will therefore get a false diagnosis of bipolar that will harm them, as it will be treated with lithium, psychosis pills, and antiepileptics.

These are serious omissions. In US, Joseph Biederman in particular has pushed the diagnosis of bipolar in children, which was virtually unknown half a century ago. He and his co-workers made a diagnosis of bipolar in 23% of 128 children with ADHD and reported this in a paper with the telling title, “Attention-Deficit Hyperactivity Disorder and Juvenile Mania: An Overlooked Comorbidity?”⁴¹⁷ There is no overlooked comorbidity, only overlooked harms.

One textbook mentioned that beta blockers, alpha blockers, prednisolone, and cytostatics can elicit and maintain both mania and depression.^17:370 In another book, the same first author, Lars Kessing, noted that beta blockers, alpha blockers, adrenal cortex hormones, and cytostatics can trigger and maintain mania; that, according to clinical experience, depression pills can trigger mania during treatment of bipolar depression; and that intoxication with central stimulants gives rise to a clinical picture that confusingly resembles mania.^16:292

This information is seriously misleading. Kessing protected psychiatry’s guild interests. He should have said that depression pills and ADHD drugs in usual dosage can cause mania or hypomania when given to anyone (even healthy volunteers).

The dramatic rise in numbers of patients with a diagnosis of bipolar disorder, previously called manic depression, is a man-made catastrophe. As noted above, this epidemic has hit children particularly hard in the United States where the prevalence rose 35-fold in just 17 years.^1:8 The fact that doctors in America make this diagnosis in children 100 times more often than in the United Kingdom⁴¹⁸ also illustrates that it is a fake diagnosis in most cases.

A US study of nearly 90,000 patients aged 5 to 29 years showed that treatment with depression pills caused a conversion rate to bipolar of about 5% a year.²⁶² A systematic review of trials in children and adolescents showed that 8% of people treated with depression pills developed mania or hypomania on the drug and only 0.2% on placebo.⁴¹⁹ A systematic review including all ages also found an 8% rate.⁴²⁰ As already noted, ADHD drugs cause symptoms that are misdiagnosed as bipolar and they can also induce bipolar disorder, as they are stimulants.

Lithium: no reliable evidence that is prevents suicide or dementia

The textbooks advised that patients with bipolar disorder should always be treated with “mood preventing [sic] drugs” (e.g. lithium),^17:371 or first be treated with lithium,^16:297 including in children from the age of 12.^19:220 For treatment-resistant depression, one book noted that augmentation with another type of drug was best documented for lithium.^16:275

I tried to find out if these recommendations are based on good evidence, but that was difficult because most trials and meta-analysis are of poor quality.

One of the better meta-analyses was about relapse prevention in bipolar disorder.⁴²¹ The authors excluded studies that randomised patients to suddenly discontinuing lithium in the placebo group, which was prudent because the cold turkey withdrawal symptoms after lithium can be severe and pronounced.^422-427 The authors reported a substantial effect of continued lithium on relapse, risk ratio 0.65 (0.50 to 0.84). However, they did not report which tapering regimes were used in the trials for those randomised to placebo, and it is therefore impossible to know if there was a true effect on relapse, or the studies just measured what happens when patients on placebo are exposed to cold turkey withdrawal. Furthermore, the criteria for relapse were very subjective and such studies are not adequately blinded. I therefore agree with the authors when they noted that “A wholly unbiased measure of average preventive efficacy would require recruitment of patients without pre-trial exposure to lithium.”

One book claimed that lithium prevents suicidal behaviour in children,^19:220 but there is no reliable evidence that this is correct.⁴²⁸ Another book claimed, without referring to age groups, that Danish and foreign studies suggest that lithium prevents suicide,^16:306 which was called a “unique anti-suicidal effect” 280 pages further ahead.^16:586

In a chapter about affective disorders, another textbook also claimed that lithium reduces the risk of suicide, according to a foreign and a Danish study.^17:376 The foreign study was not referenced but was likely a meta-analysis of the randomised trials by Cipriani and colleagues,⁴²⁹ which was not convincing (see below). Instead of referencing this study, one of the two authors quoted his own study, even though it was observational.⁴³⁰

It reported that purchasing lithium at least twice was associated with a halving of the suicide rate compared to purchasing lithium only once, a 0.44-fold reduced rate (0.28 to 0.70). This result is unreliable. The authors themselves noted that “undefined individual factors associated with acceptance and adherence to long-term treatment might tend to select for lower suicide risk during treatment” and that “nonadherence may be associated, for example, with alcoholism, drug addiction, and personality disorders that, in themselves, are associated with an increased risk of suicide.”

Furthermore, the relation between number of prescriptions and suicide was not straight-forward. The authors noted that “for men, the rate of suicide was greatest for patients purchasing lithium 2 to 5 times whereas patients who purchased lithium 6 to 10 times or 11 or more times had reduced rates as compared with patients who purchased lithium only once.” They did not present any data for this curiosity or explain how one jumps from one purchase to at least six purchases without passing the dangerous territory of two to five purchases on the way to safety.

Most importantly, although they showed data for total mortality except suicide, they did not say anything about that. I added the suicides (23 vs 79) to deaths from other causes to get total mortality rates, which were 14.7% (198/1,348) among those with only one purchase and 10.5% (1,239/11,838) among those with two or more purchases (P = 0.000006). Thus, the group with only one purchase had an extremely poor prognosis. This study is so misleading that it should never have been published.

The claim that lithium prevents suicides has a long and convoluted history. One of the books mentioned that Danish psychiatrist Mogens Schou in 1954 had included placebo in his studies. The book noted that 80% of the patients recovered,^17:910 which is misleading, as it does not take the recovery in the placebo group into account. The authors noted that Schou published his results in 1967,⁴³¹ which were later criticised for the methodology. They did not reveal what the problems were.

The lithium story started a little earlier than Schou’s studies. Australian physician John Cade fed lithium to guinea pigs and observed that it made them docile.^5:183 In 1949, he reported that he had successfully treated 10 manic patients with lithium. But he forgot to mention in his published article that he killed one patient and made two others severely ill.

In 2019, I published a systematic review with a Swedish psychiatrist about lithium’s effects on suicide and mortality.⁴²⁸ We were uncertain about whether lithium worked, whereas there was no uncertainty among psychiatric leaders. According to the 2003 practice guidelines from the American Psychiatric Association, “There is strong and consistent evidence in patients with recurring bipolar disorder and major depressive disorder that long-term maintenance treatment with lithium salts is associated with major reductions in risk of both suicide and suicide attempts.”⁴³²

A systematic review that included 37 observational studies and eight randomised trials found that the annual suicide risk was 0.4% with lithium treatment and 2.6% without lithium.⁴³³ However, confounding by indication was very likely, e.g. failure to comply with lithium treatment could be associated with a more serious condition with a worse prognosis.

In a 2013 systematic review, Andrea Cipriani and colleagues included 48 trials, 24 of which were placebo controlled, and they found that lithium reduces suicide in people with mood disorders, odds ratio 0.13 (0.03 to 0.66).⁴²⁹

However, the trials were small and there were only six suicides in total, all in the placebo group. The authors pointed out that only one or two moderately sized trials with neutral or negative results could materially affect their results. The estimate for total mortality was also uncertain, odds ratio 0.38 (0.15 to 0.95) and was based on only five deaths in the lithium groups and 14 in the placebo groups.

There are other reasons for caution. As noted earlier, about half of the deaths and half of the suicides occurring in trials of psychiatric drugs have been left out in published trial reports.¹²⁵ In order to address this problem, Cipriani et al. contacted all study authors and manufacturers. They reported that unpublished information was obtained for “most of the studies,” which was important for the outcome deliberate self-harm, for which no statistically significant benefit was found. It is not clear if the few suicides were included in this outcome, and only one trial provided data for both.⁴³⁴ Cipriani et al. did not report if their contacts with authors and companies had resulted in additional information about deaths and suicides; if all authors and manufacturers replied; or if they considered that the replies were reliable and comprehensive.

They did not explain either that they had included trials where the patients were already on lithium before they were randomised. Lithium withdrawal may trigger depression and mania,^422-427 which might explain the increased risk of suicide after lithium withdrawal.⁴²⁶ An observational study found that the median time to disease recurrence was four months after abrupt lithium discontinuation (over 1-14 days) and 20 months after more gradual discontinuation (15-30 days),⁴²⁵ which was still far too quickly.

The withdrawal effects can come quickly. In a study of 18 euthymic patients (17 with a diagnosis of bipolar disorder and one with unipolar disorder) who had received lithium for 3 to 58 months, one developed mania and two developed depression within the first four days after lithium discontinuation.⁴²² Another study found that the number of suicidal acts per year before lithium was instituted was lower than during the first year after lithium discontinuation (2.3% versus 7.1%).⁴²⁶

There were additional problems with the trials Cipriani included. It is not clear if the patients were followed up after the trial ended and if events were included from such follow-up. If people come off lithium abruptly, it will increase the risk of suicide in the lithium group. Furthermore, the review included “enriched studies,” which is a euphemism for flawed trials where only patients who respond to lithium and tolerate it are randomised.

We included 45 trials in our review where none of the patients were on lithium before they were randomised to lithium (1978 patients) or placebo (2083 patients). They covered a wide array of diagnoses and phases of the disorders, and some were therapeutic, some about preventing relapses. They were of very poor quality. Only four of the 45 eligible trials reported data on total mortality or suicides in a total of only 449 participants; the causes of deaths were not clear; and the risk of bias was high or unclear in all four trials.

In one of the trials,⁴³⁴ there were pronounced differences at baseline between the lithium and the placebo group with respect to previous suicide attempts and personality disorders. With a most remarkable statistical stunt and incorporating “available person-years” in the analysis although it was a randomised trial, the authors managed to turn three suicides versus none into a statistically significant difference (P = 0.049). We used Fisher’s Exact test on the same data, which is the appropriate analysis, and got P = 0.12.

Total mortality was significantly lower in the lithium group than in the placebo group (two versus nine deaths, odds ratio 0.28, but the 95% confidence interval was very wide, 0.08 to 0.93. If we included an additional four deaths on lithium in one of the trials that we had excluded according to our protocol because they did not have depressive comorbidity, the odds ratio was 0.70 (0.27 to 1.85). Only one study reported any suicides (none versus three); odds ratio 0.13 (0.01 to 1.27).

That lithium reduced total mortality but not suicides is the opposite of what would be expected if lithium alleviated bipolar symptoms, acute mania in particular, but with somatic harms. Our results could be related to the fact that we based our review on published trial reports. Clinical study reports likely no longer exist because lithium is a very old drug. We asked EMA that replied ten months later that they did not have them.

The investigators might think it is not important to report one or two deaths on lithium, particularly if they believe that the deaths are not related to lithium and also because psychiatrists for many years have believed that lithium saves lives. We cannot know how many deaths were missing in the 41 lithium trials where there was no information about deaths.

The answer to the question if lithium decreases the risk of suicide and total mortality is: We don’t know. New placebo-controlled trials are needed with treatment naïve patients and without any run-in period where all patients receive lithium and become stabilised on the drug. The dose titration should take place after randomisation.

To maintain the study blinding, plasma values for lithium should remain blinded for the treating physician. If there is no blinding, or inadequate blinding due to lithium’s harms, the use of other treatments, e.g. psychosis pills and electroshock, might differ in the two groups.

Trials should be very large, as suicide is a rare event, and they should last several years, as the outcome might be influenced by study length. If, for example, lithium reduces manic symptoms, it could lead to fewer accidents with a fatal outcome, but also to higher mortality in the long run because of lithium’s toxicity. Furthermore, to obtain information about long-term harms and clinical effects of lithium, trials should end with a long tapering period, and patients should be followed up for several years after they have come off the drug or placebo. Finally, the analysis of the data and the writing of the manuscript should be performed under blind conditions to reduce the risk of reporting bias;⁴³⁵ details about causes of deaths should be published; and all the raw anonymised patient data should be made freely available so that other researchers may check for themselves whether they agree with the authors.

Does lithium do more good than harm? We cannot use the four trials we found to answer that question. They had highly subjective outcomes, such as if the patients had relapsed or had improved by a certain amount, and the trials must have been poorly blinded because the harms of lithium are pronounced. If we want to know what lithium does to people, we need large trials with something in the placebo that gives adverse effects so that it is more difficult to break the blinding.

One book noted that bipolar disorder causes dementia, which can likely be prevented with medication, including lithium, which has neuroprotective properties.^18:118 Another book repeated this^{16:294,16:586} and claimed that lithium seemed to reduce or totally remove the risk of dementia.^16:294 A third book claimed that newer studies indicate that lithium has a protective effect on brain cells in bipolar patients.^17:662

There was no documentation for this wishful thinking.

One book claimed that the effect of lithium on acute mania was certain.^18:115 But what does it mean to have an effect on acute mania? There is a Cochrane review of this, which included 36 trials.⁴³⁶ It is 300 pages, the size of a book, and there are 390 analyses. This is Cochrane cookbook science at its worst. Considering how unreliable psychiatric drug trials are, and how common selective reporting is, this is way over the top.

Lithium was more effective than placebo at inducing a response, odds ratio 2.13 (1.73 to 2.63), but it was less effective than olanzapine, odds ratio 0.44 (0.20 to 0.94) and risperidone, mean difference 7.28 (5.22 to 9.34). Response is a very subjective and biased outcome in trials that are not adequately blinded, and being less effective than major tranquillisers, which do not have clinically relevant effects on psychosis, is not a convincing finding.

The Cochrane authors protected the psychiatric guild by propagating the nonsense I have debunked earlier in this book. They wrote that lithium is a neuroprotective agent in the brain that reduces cell death and enhances new neuronal growth; that functional imaging studies have shown that people treated with lithium have a global increase in grey matter, especially concentrated in the prefrontal cortex, amygdala and hippocampus, which is important because bipolar disorder may well be a neurodegenerative condition. They also wrote that lithium reduces the risk of suicide.

***

To see the list of all references cited, click here.